Multiple endocrine neoplasia type 2B

The most common clinical features of MEN2B are:{{citation needed|date=August 2020}}

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• a tall, thin, "marfanoid" body build, in which long bones are disproportionately elongated;
• masses beneath mucosal surfaces in the mouth, lips, and eyes (discussed below);
• low muscle mass, sometimes with myopathy;
• gastrointestinal complaints, especially constipation;
• symptoms derived from medullary carcinoma of the thyroid;
• symptoms derived from pheochromocytoma;
• craniosynostosis;
• dry eyes or lack of tears;
• delayed puberty.

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File:Mucosal Neuromas.png

Unlike Marfan syndrome, the cardiovascular system and the lens of the eye are unaffected.{{citation needed|date=January 2017}} Mucosal neuromas are the most consistent and distinctive feature, appearing in 100% of patients.{{cite journal |vauthors=Pujol RM, Matias-Guiu X, Miralles J, Colomer A, de Moragas JM |title=Multiple idiopathic mucosal neuromas: a minor form of multiple endocrine neoplasia type 2B or a new entity? |journal=J. Am. Acad. Dermatol. |volume=37 |issue=2 Pt 2 |pages=349–52 |date=August 1997 |pmid=9270546 |doi=10.1016/S0190-9622(97)70025-2 }} Usually there are numerous yellowish-white, sessile, painless nodules on the lips or tongue, with deeper lesions having normal coloration. There may be enough neuromas in the body of the lips to produce enlargement and a "blubbery lip" appearance. Similar nodules may be seen on the sclera and eyelids.{{citation needed|date=August 2020}}

Histologically, neuromata contain a characteristic adventitious plaque of tissue composed of hyperplastic, interlacing bands of Schwann cells and myelinated fibers overlay the posterior columns of the spinal cord.{{Cite journal|title=Multiple endocrine neoplasia, type 2b: phenotype recognition; neurological features and their pathological basis |last=Dyck |first=PJ |journal= Annals of Neurology |date=October 1979 |volume=6 |issue=4 |pages=302–314 |pmid=554522|doi=10.1002/ana.410060404|s2cid=24328061 }} Mucosal neuromas are made up of nerve cells, often with thickened perineurium, intertwined with one another in a plexiform pattern. This tortuous pattern of nerves is seen within a background of loose endoneurium-like fibrous stroma.{{citation needed|date=August 2020}}

Variations in the RET proto-oncogene cause MEN2B. In recent decades no case of MEN2B has been reported that lacks such a variation. The M918T variant alone is responsible for approximately 95% of cases.{{Cite book|url=https://books.google.com/books?id=jIxXJCxGNvAC&pg=PT264 |pages=246–7 |title=Pediatric Endocrinology |first= Mark A. |last=Sperling |edition=3 |publisher=Elsevier Health Sciences |year=2008 |isbn=978-1-4160-4090-3 }} All DNA variants that cause MEN2B are thought to enhance signaling through the RET protein, which is a receptor molecule found on cell membranes, whose ligands are part of the transforming growth factor beta signaling system.{{citation needed|date=August 2020}}

About half of cases are inherited from a parent as an autosomal dominant trait. The other half appear to be spontaneous mutations, usually arising in the paternal allele,{{cite journal |vauthors=Morrison PJ, Nevin NC |title=Multiple endocrine neoplasia type 2B (mucosal neuroma syndrome, Wagenmann-Froboese syndrome) |journal=J. Med. Genet. |volume=33 |issue=9 |pages=779–82 |date=September 1996 |pmid=8880581 |pmc=1050735 |doi=10.1136/jmg.33.9.779 }} particularly from older fathers. The sex ratio in de novo cases is also uneven: sons are twice as likely to develop MEN 2B as daughters.

DNA testing is now the preferred method of establishing a diagnosis for MEN 2B, and is thought to be almost 100% sensitive and specific. Gordon et al. reported cases of a difference disease—the "multiple mucosal neuroma syndrome"—having the physical phenotype of MEN2B, but without variations in the RET gene and without malignancy.{{cite journal | author = Gordon CM, Majzoub JA, Marsh DJ, Mulliken JB, Ponder BA, Robinson BG, Eng C |author-link6=Bruce Robinson (endocrinologist) | date = Jan 1998 | title = Four cases of mucosal neuroma syndrome: multiple endocrine neoplasm 2B or not 2B? | journal = J Clin Endocrinol Metab | volume = 83 | issue = 1| pages = 17–20 | doi = 10.1210/jcem.83.1.4504 | pmid = 9435410 | doi-access = free }}

MEN2B should be entertained as a diagnosis whenever a person is found to have either medullary thyroid carcinoma or pheochromocytoma. Before DNA testing became available, measurement of serum calcitonin was the most important laboratory test for MEN2B. Calcitonin is produced by the "C" cells of the thyroid, which, because they are always hyperplastic or malignant in MEN2B, produce more calcitonin than normal. Calcitonin levels remain a valuable marker to detect recurrence of medullary thyroid carcinoma after thyroidectomy.{{citation needed|date=August 2020}}

Luxol fast blue staining identifies myelin sheathing of some fibers, and lesional cells react immunohistochemically for S-100 protein, collagen type IV, vimentin, NSE, and neural filaments. More mature lesions will react also for EMA, indicating a certain amount of perineurial differentiation. Early lesions, rich in acid mucopolysaccharides, stain positively with alcian blue. When medullary thyroid cancer is present, levels of the hormone calcitonin are elevated in serum and urine. Under the microscope, tumors may closely resemble traumatic neuroma, but the streaming fascicles of mucosal neuroma are usually more uniform and the intertwining nerves of the traumatic neuroma lack the thick perineurium of the mucosal neuroma.{{Cite journal|url=http://www3.interscience.wiley.com/journal/119632940/abstract |archive-url=https://archive.today/20121013001709/http://www3.interscience.wiley.com/journal/119632940/abstract |url-status=dead |archive-date=13 October 2012 |title= The ultrastructure of oral neuromas in multiple mucosal neuromas, pheochromocytoma, medullary thyroid carcinoma syndrome |author1=R. L. Miller |author2=N. J. Burzynski |author3=B. L. Giammara |journal=Journal of Oral Pathology & Medicine |year=1977 |volume=6 |issue= 5 |pages=253–63 |doi= 10.1111/j.1600-0714.1977.tb01647.x |pmid=409817 }} Inflammatory cells are not seen in the stroma and dysplasia is not present in the neural tissues.{{citation needed|date=May 2022}}

Without treatment, persons with MEN2B die prematurely. Details are lacking, owing to the absence of formal studies, but it is generally assumed that death in the 30s is typical unless prophylactic thyroidectomy and surveillance for pheochromocytoma are performed (see below). The range is quite variable, however: death early in childhood can occur, and a few untreated persons have been diagnosed in their 50s.{{cite journal |vauthors=Sizemore GW, Carney JA, Gharib H, Capen CC |title=Multiple endocrine neoplasia type 2B: eighteen-year follow-up of a four-generation family |journal=Henry Ford Hosp Med J |year=1992 |volume=40 |pages=236–244 |pmid=1362413 |issue=3–4}} Recently, a larger experience with the disease "suggests that the prognosis in an individual patient may be better than previously considered."{{cite book |last1=Hoff |first1=AO |last2=Gagel |first2=RF |chapter=Chapter 192: Multiple endocrine neoplasia type 2 |editor1-last=DeGroot |editor1-first=LJ |editor2-last=Jameson |editor2-first=JL |title=Endocrinology |edition=5th |year=2006 |location=Philadelphia |publisher=Elsevier-Saunders |pages=[https://archive.org/details/endocrinology0003unse/page/3533 3533–3550] |isbn=978-0721603766 |chapter-url=https://archive.org/details/endocrinology0003unse/page/3533 }}

Thyroidectomy is the mainstay of treatment, and should be performed without delay as soon as a diagnosis of MEN2B is made, even if no malignancy is detectable in the thyroid. Without thyroidectomy, almost all patients with MEN2B develop medullary thyroid cancer, in a more aggressive form than MEN 2A.{{Cite book|url=https://books.google.com/books?id=Q2SP8cOZPvkC&pg=PA141 |pages=141 |title=Burket's oral medicine |author1=Lester W. Burket |author2=Martin S. Greenberg |author3=Michaël Glick |author4=Jonathan A. Ship |edition=11 |publisher=PMPH-USA |year=2008 |isbn=978-1-55009-345-2 }} The ideal age for surgery is 4 years old or younger, since cancer may metastasize before age 10.

Pheochromocytoma - a hormone secreting tumor of the adrenal glands - is also present in 50% of cases. Affected individuals are encouraged to get yearly screenings for thyroid and adrenal cancer.{{citation needed|date=August 2020}}

Because prophylactic thyroidectomy improves survival, blood relatives of a person with MEN2B should be evaluated for MEN2B, even if lacking the typical signs and symptoms of the disorder.{{citation needed|date=January 2017}}The mucosal neuromas of this syndrome are asymptomatic and self-limiting, and present no problem requiring treatment. They may, however, be surgically removed for aesthetic purposes or if they are being constantly traumatized.{{citation needed|date=October 2021}}

In 2007, Dr. John Sotos proposed that President Abraham Lincoln had MEN2B.{{cite book|author=Sotos, JG|title=The Physical Lincoln: Finding the Genetic Cause of Abraham Lincoln's Height, Homeliness, Pseudo-Depression, and Imminent Cancer Death|location=Mount Vernon, VA|publisher=Mt. Vernon Book Systems|year=2008|url=http://www.physical-lincoln.com/}} This theory suggests Lincoln had all the major features of the disease: a marfan-like body habitus, large, bumpy lips, constipation, muscular hypotonia, a history compatible with cancer, a family history of signs suggestive of the disorder (in his sons Eddie, Willie, and Tad, and probably his mother). The "mole" on Lincoln's right cheek, the asymmetry of his face, his large jaw, his drooping eyelid, and "pseudo-depression" are also suggested as manifestations of MEN2B. Lincoln's relative longevity (dying at 56 of a gunshot wound) is the principal challenge to the MEN2B theory, although Lincoln did make oblique references to ill health prior to his death. As a result, whether Lincoln had MEN2B remains an open question and could only be proven definitively by DNA testing.[http://blogs.discovermagazine.com/80beats/2009/04/20/scientist-wants-to-test-abraham-lincolns-bloodstained-pillow-for-cancer/ Scientist Wants to Test Abraham Lincoln's Bloodstained Pillow for Cancer] Discover Magazine 20 April 2009Lincoln's Shroud of Turin, Philadelphia Inquirer, 13 April 2009

• Multiple endocrine neoplasia
• Multiple endocrine neoplasia type 1
• Multiple endocrine neoplasia type 2a

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| OMIM = 162300

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{{Disorders involving multiple endocrine glands}}

{{Endocrine gland neoplasia}}

{{DEFAULTSORT:Multiple Endocrine Neoplasia Type 2b}}

Category:Hereditary cancers

Category:Endocrine neoplasia

Category:Endocrine-related cutaneous conditions

Category:Autosomal dominant disorders